Wnt/β-catenin signalling:function,biological mechanisms,and therapeutic opportunities

The Wnt/β-catenin pathway comprises a family of proteins that play critical roles in embryonic development and adult tissue homeostasis.The deregulation of Wnt/β-catenin signalling often leads to various serious diseases,including cancer and non-cancer diseases.Although many articles have reviewed Wnt/β-catenin from various aspects,a systematic review encompassing the origin,composition,function,and clinical trials of the Wnt/β-catenin signalling pathway in tumour and diseases is lacking.In this article,we comprehensively review the Wnt/β-catenin pathway from the above five aspects in combination with the latest research.Finally,we propose challenges and opportunities for the development of small-molecular compounds targeting the Wnt signalling pathway in disease treatment.

Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer

Oxaliplatin is widely used in the frontline treatment of colorectal cancer(CRC),but an estimated 50%of patients will eventually stop responding to treatment due to acquired resistance.This study revealed that diminished MEIS1 expression was detected in CRC and harmed the survival of CRC patients.MEIS1 impaired CRC cell viabilities and tumor growth in mice and enhanced CRC cell sensitivity to oxaliplatin by preventing DNA damage repair.Mechanistically,oxaliplatin resistance following MEIS1 suppression was critically dependent on enhanced FEN1 expression.Subsequently,we confirmed that EZH2-DNMT3a was assisted by lncRNA ELFN1-AS1 in locating the promoter of MEIS1 to suppress MEIS1 transcription epigenetically.Based on the above,therapeutics targeting the role of MEIS1 in oxaliplatin resistance were developed and our results suggested that the combination of oxaliplatin with either ELFN1-AS1 ASO or EZH2 inhibitor GSK126 could largely suppress tumor growth and reverse oxaliplatin resistance.This study highlights the potential of therapeutics targeting ELFN1-AS1 and EZH2 in cell survival and oxaliplatin resistance,based on their controlling of MEIS1 expression,which deserve further verification as a prospective therapeutic strategy.

Cyclophilin A binds to AKT1 and facilitates the tumorigenicity of Epstein-Barr virus by mediating the activation of AKT/mTOR/NF-κB positive feedback loop

The AKT/mTOR and NF-κB signalings are crucial pathways activated in cancers including nasopharyngeal carcinoma(NPC), which is prevalent in southern China and closely related to Epstein-Barr virus(EBV) infection.How these master pathways are persistently activated in EBV-associated NPC remains to be investigated. Here we demonstrated that EBV-encoded latent membrane protein 1(LMP1) promoted cyclophilin A(CYPA) expression through the activation of NF-κB. The depletion of CYPA suppressed cell proliferation and facilitated apoptosis.CYPA was able to bind to AKT1, thus activating AKT/mTOR/NF-κB signaling cascade. Moreover, the use of mTOR inhibitor, rapamycin, subverted the activation of the positive feedback loop, NF-κB/CYPA/AKT/mTOR. It is reasonable that LMP1 expression derived from initial viral infection is enough to assure the constant potentiation of AKT/mTOR and NF-κB signalings. This may partly explain the fact that EBV serves as a tumor-promoting factor with minimal expression of the viral oncoprotein LMP1 in malignancies. Our findings provide new insight into the understanding of causative role of EBV in tumorigenicity during latent infection.